Natural products which contain chiral alpha-branched amine substructures, and their unnatural analogs available only through synthesis, are critically important for medical research. For example, tubulysins are newly discovered anticancer agents with unusual chemical structures and extraordinary potency, and therefore represent a new lead in the search for novel experimental synthetic drugs for chemotherapy. In the specific aims proposed, amine-containing natural products will be synthesized as the first tests of newly developed asymmetric carbon-carbon bond construction methodology in complex molecule synthesis. Novel asymmetric free radical addition, tandem cyclization, hybrid radical-ionic annulation, and allylsilane addition reactions of chiral hydrazones will be used. Synthesis targets include tubulysins (picomolar antimitotic agents), dysiherbaine (non-NMDA glutamate receptor agonist), azasugars (glycosidase inhibitors), quinine (antimalarial agent), and lasubine II (subunit of bioactive quinolizidines). Success in the proposed program has potential to increase overall efficiency in syntheses of medicinally important compounds, a broad and general contribution to the science of organic chemistry which provides critical enabling technology for health sciences research. The projects also provide excellent training to prepare new researchers for productive careers in health-related fields. In the long term, these endeavors will advance the art and science of synthetic organic chemistry toward the ideal of efficiency, a long-term goal which remains mostly inaccessible in syntheses of complex natural products.